# NM_014845.6(FIG4):c.2559G>A (p.Ser853=)

https://sugi.bio/variant/fig4-p-ser853

## Summary

**FIG4 p.Ser853= (c.2559G>A)** is classified **Benign/Likely benign** in FIG4 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). Common (popmax 56.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Charcot-Marie-Tooth disease.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs1127771 · 13 submitters · 6 linked conditions · common (popmax 56.9%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the FIG4 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 13 submitters, and is linked to Charcot-Marie-Tooth disease.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 59 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006034/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FIG4](https://sugi.bio/atlas/gene/FIG4/) |
| Protein change (HGVS p.) | p.Ser853= |
| Coding change (HGVS c.) | c.2559G>A |
| MANE Select transcript | [NM_014845](https://www.ncbi.nlm.nih.gov/nuccore/NM_014845) |
| dbSNP | [rs1127771](https://www.ncbi.nlm.nih.gov/snp/rs1127771/) |
| Variant type | single nucleotide variant |
| Location | chr6:109825100-109825100 (GRCh38) |
| ClinVar | [VCV260449](https://www.ncbi.nlm.nih.gov/clinvar/variation/260449/) |

**All HGVS expressions:** `LRG_241:g.138880G>A`, `LRG_241t1:c.2559G>A`, `NC_000006.11:g.110146303G>A`, `NC_000006.12:g.109825100G>A`, `NG_007977.1:g.138880G>A`, `NM_014845.6:c.2559G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 56.9%, eas) — too common for a highly-penetrant pathogenic allele.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -5.248, GERP -3.77 — fast-evolving / accelerated position
- CADD: **PHRED 0.166**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **56.9%** (eas) · FAF95 56.3% · FAF99 56.1% · 25,522/44,844 in the highest group · 669,688/1,611,466 alleles overall — common (popmax 56.9%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 56.9% | 2 |
| South Asian | 54.8% | 2 |
| Admixed American | 49% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 48.4% | 2 |
| Middle Eastern | 46% | 2 |
| Remaining individuals (not grpmax-eligible) | 43.6% | 2 |
| Finnish (not grpmax-eligible) | 41.9% | 2 |
| European (non-Finnish) | 41% | 2 |
| Amish (not grpmax-eligible) | 38.4% | 3 |
| African / African-American | 14.4% | 7 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**FIG4** population constraint: LOEUF 0.966, pLI 1.3237e-16, missense-Z 1.7961. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Charcot-Marie-Tooth disease** — Definitive (AR)
- **amyotrophic lateral sclerosis type 11** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.65, 50% of residues very-high.

**1 experimental structure(s)** (PDB): [7K1W](https://www.rcsb.org/structure/7K1W).

## What this gene does {#gene-function}

*Describes the biological roles of FIG4 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

FIG4 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of PIPs at the Golgi membrane](https://reactome.org/content/detail/R-HSA-1660514) | electronic |
| [Synthesis of PIPs at the early endosome membrane](https://reactome.org/content/detail/R-HSA-1660516) | electronic |
| [Synthesis of PIPs at the late endosome membrane](https://reactome.org/content/detail/R-HSA-1660517) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate metabolic process.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (16 Benign, 1 Likely benign).

**Submission history:** 17 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Benign | no assertion criteria provided | clinical testing |  |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-08-10 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Molecular Genetics Laboratory, London Health Sciences Centre | Benign | criteria provided, single submitter | clinical testing |  |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2015-08-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Benign | no assertion criteria provided | clinical testing |  |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease/), [Yunis-Varon syndrome](https://sugi.bio/atlas/disease/yunis-varon-syndrome/), [Charcot-Marie-Tooth disease type 4J](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-4j/), [amyotrophic lateral sclerosis type 11](https://sugi.bio/atlas/disease/amyotrophic-lateral-sclerosis-type-11/), [bilateral parasagittal parieto-occipital polymicrogyria](https://sugi.bio/atlas/disease/bilateral-parasagittal-parieto-occipital-polymicrogyria/), [Charcot-Marie-Tooth disease type 4](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-4/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease, not specified, Amyotrophic lateral sclerosis type 11, Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease type 4J, Yunis-Varon syndrome, Bilateral parasagittal parieto-occipital polymicrogyria, not provided, Charcot-Marie-Tooth Hereditary Neuropathy, Charcot-Marie-Tooth Neuropathy.

## Similar variants {#similar}

Related FIG4 variant pages (same residue, condition, or type): [FIG4 p.Ser853Leu](/variant/fig4-p-ser853leu), [FIG4 c.1040-1G>A](/variant/fig4-c-1040-minus-1g-a), [FIG4 c.1584-1G>T](/variant/fig4-c-1584-minus-1g-t), [FIG4 c.1948+1G>A](/variant/fig4-c-1948-plus-1g-a), [FIG4 c.1949-10T>G](/variant/fig4-c-1949-minus-10t-g), [FIG4 c.2376+2T>G](/variant/fig4-c-2376-plus-2t-g), [FIG4 c.2459+1G>A](/variant/fig4-c-2459-plus-1g-a), [FIG4 c.877-2A>C](/variant/fig4-c-877-minus-2a-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 260449). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*